Project Summary/Abstract This revised K08 proposal will complete Graham Brady, MD, PhD's training toward his goal of improving our understanding and treatment of nonalcoholic fatty liver disease (NAFLD). Dr. Brady is a physician and scientist in hepatology at the University of Michigan with clinical expertise in liver disease, graduate training in cell biology and biochemistry, and established success in the field of NAFLD. This proposal builds on Dr. Brady's prior experience, with new training in genomics, bioinformatics, and a unique model organism (zebrafish). His existing expertise and newly-acquired skills will be integrated to advance our understanding of the scope and mechanisms of nuclear lamina-related NAFLD. The research will be conducted under the guidance of primary mentor Bishr Omary, MD, PhD, and co-mentors Liz Speliotes, MD, PhD, MPH, and Jordan Shavit, MD, PhD, with Jun Li, PhD, as a collaborator, who have expertise in NAFLD, genomics, zebrafish, and extensive mentoring success. The 5-year career development plan includes formal coursework, professional development, and mentored research, with defined milestones to ensure productivity and a successful transition to independence. The estimated global prevalence of NAFLD is now ~25%, but medical therapies are limited in number and efficacy, partly due to incomplete understanding of its pathogenesis. A unique group of patients with mutations in genes encoding nuclear lamina components develop early-onset NAFLD that often progresses to steatohepatitis (NASH) with cirrhosis. Mechanisms of NAFLD/NASH due to nuclear lamina mutations are obscure, but their study may provide insights into NAFLD pathogenesis and avenues for future therapies. This proposal will test the hypothesis that genetic alteration of the nuclear lamina predisposes to NAFLD/NASH by altering nuclear protein organization and the transcriptome. The mentored research has two Specific Aims: ? AIM 1: Identify and validate variants in nuclear lamina-related genes in NAFLD/NASH cohorts. ? AIM 2: Establish new experimental models to study how LMNA variants alter the nuclear lamina, heterochromatin, and transcriptome to promote NAFLD/NASH. In completing these aims, Dr. Brady will analyze genomic data linked to electronic medical record data in unique NAFLD cohorts and develop new disease models that will provide mechanistic insights into lamina- related NAFLD and in vivo systems for drug screening. This will build to two R01 proposals: (1) to examine the mechanistic basis of NAFLD-associated variants identified in AIM 1 and (2) to examine the mechanisms and therapeutic potential of screened compounds in the models generated in AIM 2. In addition to building a foundation for a programmatic line of research to understand the role of the nuclear envelope in liver disease, this K08 will provide Dr. Brady with research skills applicable to additional domains of hepatology and genomics and equip him to establish himself as an independent investigator and leader in this field.